Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease

Jean-Pierre Hugot, Mathias Chamaillard, Habib Zouali, Suzanne Lesage, Jean-Pierre Cézard, Jacques Belaiche, Sven Almer, Curt Tysk, Colm A. O'Morain, Miquel Gassull, Vibeke Binder, Yigael Finkel, Antoine Cortot, Robert Modigliani, Pierre Laurent-Puig, Corine Gower-Rousseau, Jeanne Macry, Jean-Frédéric Colombel, Mourad Sahbatou and Gilles Thomas ()
Additional contact information
Jean-Pierre Hugot: Fondation Jean Dausset CEPH
Mathias Chamaillard: Fondation Jean Dausset CEPH
Habib Zouali: Fondation Jean Dausset CEPH
Suzanne Lesage: Fondation Jean Dausset CEPH
Jean-Pierre Cézard: PEWG-IBD, Hôpital Robert Debré
Jacques Belaiche: CHU de Liège
Sven Almer: IHM, Linköpings Universitet
Curt Tysk: Örebro Medical Center Hospital
Colm A. O'Morain: Adelaide & Meath Hospital
Miquel Gassull: Hospital Universitari Germans Trias i Pujol
Vibeke Binder: Department of Gastroenterology Herlev Hospital
Yigael Finkel: Astrid Lindgren Children′s Hospital
Antoine Cortot: Registre EPIMAD, Hôpital Calmette
Robert Modigliani: Hopital Saint Louis
Pierre Laurent-Puig: INSERM U434
Corine Gower-Rousseau: Registre EPIMAD, Hôpital Calmette
Jeanne Macry: INSERM U458, Hôpital Robert Debré
Jean-Frédéric Colombel: Registre EPIMAD, Hôpital Calmette
Mourad Sahbatou: Fondation Jean Dausset CEPH
Gilles Thomas: Fondation Jean Dausset CEPH

Nature, 2001, vol. 411, issue 6837, 599-603

Abstract: Abstract Crohn's disease1,2 and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped3 to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Date: 2001
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DOI: 10.1038/35079107

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